Serotonin is a neurotransmitter in the brain that plays an important role in complex behaviors including addiction. We have previously shown that 5-HT1B receptors alter brain reward mechanisms that play a central role in addiction;these receptors also seem to be involved in the adaptation to stress. Since stress can facilitate drug craving and relapse to drug seeking after abstinence, we will examine the role of this receptor using rodent models of drug addiction. In the initial five years of this grant, we established that the regional expression of 5-HT1B receptors is a critical determinant of their effects on behaviors associated with addiction. An overriding theme in the coming years is to identify the stages at which these receptors play key roles in addiction. We will use strategies that combine molecular and behavioral approaches to investigate the function of 5-HT1B receptors in nucleus accumbens projection neurons, a key component in the brain reward and habit formation systems. We hypothesize that increased 5-HT1B expression is an allostatic adaptation to chronic stress that ameliorates mood disturbance yet facilitates drug addiction. Aim 1 investigates the temporal association between social defeat stress and 5-HT1B gene expression in dorsal and ventral striatum. We will therefore investigate whether experimentally increased 5-HT1B receptor expression using viral mediated gene transfer reduces the impact of social defeat stress on hedonic state, and whether expression knockdown exacerbates stress-induced changes in the same behavior. In Aim 2 we will determine whether increased 5-HT1B expression modulates the motivation to self administer cocaine at several key stages, using animal models that capture the developmental progression inherent to addiction. These two Aims constitute a two-pronged strategy investigating the bidirectional relationship between behavioral stress experience and gene expression that impact hedonic state and the propensity to self-administer cocaine.